A gradual decline in renal function occurs in healthy aging individuals. Aging may exacerbate Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD). About more than half of the CKD cases and majority of the end stage renal disease (ESRD) occur in the older population. These findings highlight the importance of kidney aging and its potential contribution to AKI, CKD and ESRD in the elderly. Since the population older than 65 years in the United States is expected to double during the next 20 years, focus on potential early intervention strategies for age-associated renal injury and disease becomes critical. We will test the hypothesis that the age-related decreases in nuclear hormone receptor FXR and G protein coupled membrane receptor TGR5 expression play an important role in age-related kidney disease by impairing mitochondrial function, which results in a) increased generation of mitochondrial reactive oxygen species (ROS) and decreased generation of mitochondrial antioxidants, causing increased oxidative stress and inflammation, and b) decreased mitochondrial fatty acid -oxidation, causing increased renal lipid accumulation. We propose that FXR and/or TGR5 agonists or overexpression will prevent or markedly reduce age-related decline in glomerular filtration rate (GFR), increase in albuminuria, podocyte loss, and accumulation of extracellular matrix proteins (fibrosis) by improving mitochondrial function, which results in a) decreased generation of mitochondrial reactive oxygen species (ROS) and increased generation of mitochondrial antioxidants, causing decreased oxidative stress and inflammation, and b) increased mitochondrial fatty acid -oxidation, causing decreased renal lipid accumulation. In SPECIFIC AIM 1, we will determine the role of FXR and TGR5 in progression of age-related renal disease. We will also perform mechanistic studies to determine how alterations in kidney bile acid composition regulate podocyte function. In SPECIFIC AIM 2, we will perform mechanistic studies to determine if FXR and TGR5 protect against age-related renal disease by Sirtuin 3 dependent mechanisms. Impact and Innovation: 1) The hitherto unrecognized roles of: i) nuclear receptor FXR, ii) G protein coupled receptor TGR5 and iii) the potential of dual FXR/TGR5 agonists as therapeutic agents for treating age- associated renal disease and complications. 2) The novel and distinct role of FXR and TGR5 agonists in regulation of mitochondrial function, oxidative stress, inflammation, and lipid metabolism, as they relate to age- associated renal conditions. 3) TGR5/FXR signaling mimics that of caloric restriction (CR), potentially leading to new intervention strategies for age-related kidney injury and complications. 4) Mechanistic studies to determine the roles of the bile acids and mitochondrial Sirtuin 3 in modulation of age-related renal disease.